Pharmacokinetic interactions between fexuprazan, a potassium-competitive acid blocker, and nonsteroidal anti-inflammatory drugs in healthy males.

Fexuprazan, a novel potassium-competitive acid blocker, is expected to be used for the prevention of nonsteroidal anti-inflammatory drugs (NSAIDs) induced ulcer. This study aimed to evaluate pharmacokinetic (PK) interactions between fexuprazan and NSAIDs in healthy subjects. A randomized, open-label, multicenter, six-sequence, one-way crossover study was conducted in healthy male subjects. Subjects randomly received one of the study drugs (fexuprazan 40 mg BID, celecoxib 200 mg BID, naproxen 500 mg BID, or meloxicam 15 mg QD) for 5 or 7 days in the first period followed by the combination of fexuprazan and one of NSAIDs for the same days and the perpetrator additionally administered for 1-2 days in the second period. Serial blood samples for PK analysis were collected until 48- or 72-h post-dose at steady state. PK parameters including maximum plasma concentration at steady state (Cmax,ss) and area under plasma concentration-time curve over dosing interval at steady state (AUCτ,ss) were compared between monotherapy and combination therapy. The PKs of NSAIDs were not significantly altered by fexuprazan. For fexuprazan, differences in PK parameters (22% in Cmax, 19% in AUCτ,ss) were observed when co-administered with naproxen, but not clinically significant. The geometric mean ratio (90% confidence interval) of combination therapy to monotherapy for Cmax,ss and AUCτ,ss was 1.22 (1.02-1.46) and 1.19 (1.00-1.43), respectively. There were no significant changes in the systemic exposure of fexuprazan by celecoxib and meloxicam. Fexuprazan and NSAIDs did not show clinically meaningful PK interactions.

Bioequivalence of Celecoxib Capsules in Chinese Healthy Volunteers.

Celecoxib is a sulfanilamide nonsteroidal anti-inflammatory drug that can selectively inhibit cyclooxygenase-2 to inhibit prostaglandin production, achieving anti-inflammatory and analgesic effects. This study investigated the pharmacokinetics, safety, and bioequivalence of a single oral dose of celecoxib capsule (the test or reference preparation) in healthy volunteers under fasting and fed conditions. A single-center, randomized, open, single-dose, double-cycle crossover self-control design was conducted: 40 healthy volunteers were enrolled in the fasting and fed groups, respectively. A completely randomized method was used, with one group taking the test celecoxib preparation (T) and the other taking the reference celecoxib preparation (R). During the administration period, the safety of the drug was evaluated simultaneously, and venous blood was collected at the corresponding time points. The concentration of celecoxib in plasma was measured by liquid chromatography-tandem mass spectrometry. The main pharmacokinetic parameters were logarithmically converted and analyzed for variance. The 90% confidence interval for the bioavailability of the T compared to the R was calculated using maximum drug plasma concentration, area under the plasma concentration-time curve from time zero to the last quantifiable concentration point, and area under the plasma concentration-time curve from time zero to infinity for a single oral dose in volunteers, and the data obtained were all between 80% and 125%, indicating that the T and R have bioequivalence and good safety during fasting and fed administration.

Celecoxib Colorectal Bioavailability and Chemopreventive Response in Patients with Familial Adenomatous Polyposis.

Why celecoxib exerts chemopreventive activity in only some familial adenomatous polyposis (FAP) patients remains poorly understood. We conducted a phase II clinical study to identify potential predictive biomarkers for celecoxib chemopreventive activity in FAP. Twenty-seven patients with FAP completed a 6-month oral course of 400 mg of celecoxib twice a day; they underwent colonoscopies before and after celecoxib treatment to assess colorectal polyp tumor burden and to obtain normal and polyp colorectal biopsies to measure celecoxib, 13-S-hydroxyoctadecadienoic acid (13-HODE), 15-HETE, 12-HETE, and LTB4 levels by LC/MS-MS. Celecoxib levels in sera from those patients were also measured before treatment and after 2, 4, and 6 months of treatment. Nineteen of the 27 patients experienced a response to celecoxib, with a ≥ 28% reduction of colonic polyp burden on the basis of a reproducible quantitative assessment of colonoscopy results. Celecoxib levels were significantly lower in polyp tissues than in normal colorectal tissues. Celecoxib levels in sera and normal colorectal tissues were correlated in patients who experienced a response to celecoxib but not in those who did not. Among the measured lipoxygenase products, only 13-HODE levels were significantly lower in polyp tissues than in normal tissues. Our findings demonstrate the differential bioavailability of celecoxib between normal and polyp tissues and its potential effects on clinical response in patients with FAP. PREVENTION RELEVANCE: This study evaluated potential predictive biomarkers for celecoxib chemopreventive activity in patients with FAP. Our findings demonstrated the differential bioavailability of celecoxib between normal and polyp tissues and its potential effects on clinical chemopreventive response in patients with FAP. See related Spotlight, p. 205.

Increasing the Transport of Celecoxib over a Simulated Intestine Cell Membrane Model Using Mesoporous Magnesium Carbonate.

In the current work, mesoporous magnesium carbonate (MMC) was used to suppress crystallization of the poorly soluble drug celecoxib (CXB). This resulted in both a higher dissolution rate and supersaturation of the substance in vitro as well as an increased transfer of CXB over a Caco-2 cell membrane mimicking the membrane in the small intestine. The CXB flux over the cell membrane showed a linear behavior over the explored time period. These results indicate that MMC may be helpful in increasing the bioavailability and obtaining a continuous release of CXB, and similar substances, in vivo. Neusilin US2 was used as a reference material and showed a more rapid initial release with subsequent crystallization of the incorporated CXB in the release media. The presented results form the foundation of future development of MMC as a potential carrier for poorly soluble drugs.

Tailoring Release Profiles of BCS Class II Drugs Using Controlled Release Amorphous Solid Dispersion Beads with Membrane-Reservoir Design: Effect of Pore Former and Coating Levels.

Poor aqueous solubility is a major limiting factor during the development of BCS Class II drug candidates in a solid oral dosage form. Conventional amorphous solid dispersion (ASD) systems focus on maximizing the rate and extent of release by employing water-soluble polymeric crystallization inhibitors; however, they often encounter rapid supersaturation and solution-mediated phase transformation (SMPT). Therefore, in this work, a controlled release membrane was introduced onto ASD beads to mitigate the SMPT problem. A membrane-reservoir controlled release amorphous solid dispersion (CRASD) bead system was designed, and the effects of the coating thickness and pore former content on drug release profiles were investigated. CRASD beads were manufactured by spray-coating polyvinyl acetate with polyvinylpyrollidone (PVP) as a pore former onto sugar bead substrates layered with the ASD reservoir of celecoxib and PVP. Raising the pore former content and/or lowering the coating level imparted higher release rates and supersaturation levels. The extent of release, measured by the area under the curve, was greatest when an optimal balance between the release rate and peak concentration could be established, corresponding to a high pore former/high coating level combination. Attributed to a thicker membrane structure with a higher pore former, rapid initial release could be achieved, yet controlled gradually for several hours, avoiding the critical threshold where the onset of SMPT predominates. The greater membrane capacity to transiently immobilize drug molecules (i.e., preserve amorphicity) and gradually release drug over a prolonged duration may be key to balancing supersaturation on both sides of the membrane; hence coating variables should be tactfully selected to exploit this benefit.

Physiologically based pharmacokinetic (PBPK) modeling for prediction of celecoxib pharmacokinetics according to CYP2C9 genetic polymorphism.

Celecoxib is a non-steroidal anti-inflammatory drug (NSAID) and a representative selective cyclooxygenase (COX)-2 inhibitor, which is commonly prescribed for osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute pain, and primary dysmenorrhea. It is mainly metabolized by CYP2C9 and partly by CYP3A4 after oral administration. Many studies reported that CYP2C9 genetic polymorphism has significant effects on the pharmacokinetics of celecoxib and the occurrence of adverse drug reactions. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model of celecoxib according to CYP2C9 genetic polymorphism for personalized pharmacotherapy. Initially, a clinical pharmacokinetic study was conducted where a single dose (200 mg) of celecoxib was administered to 39 healthy Korean subjects with CYP2C9*1/*1 or CYP2C9*1/*3 genotypes to obtain data for PBPK development. Based on the conducted pharmacokinetic study and a previous pharmacokinetic study involving subjects with CYP2C9*1/*13 and CYP2C9*3/*3 genotype, PBPK model for celecoxib was developed. A PBPK model for CYP2C9*1/*1 genotype group was developed and then scaled to other genotype groups (CYP2C9*1/*3, CYP2C9*1/*13 and CYP2C9*3/*3). After model development, model validation was performed with comparison of five pharmacokinetic studies. As a result, the developed PBPK model of celecoxib successfully described the pharmacokinetics of each CYP2C9 genotype group and its predicted values were within the acceptance criterion. Additionally, all the predicted values were within two-fold error range in comparison to the previous pharmacokinetic studies. This study demonstrates the possibility of determining the appropriate dosage of celecoxib for each individual through the PBPK modeling with CYP2C9 genomic information. This approach could contribute to the reduction of adverse drug reactions of celecoxib and enable precision medicine.

Fabrication and Evaluation of Celecoxib Oral Oleogel to Reduce the Inflammation of Ulcerative Colitis.

Oleogel consists of hydrophobic solvent and an oleogelator. In this study, attempts were made to study the influence of Celecoxib solubility, concentration and dispersability on its release, absorption, and biological performance. Oleogels were prepared to study the formulation variables on its stability and release. Castor oil was selected as the oil and the oleogelator concentration was 4.5% w/w. F3 revealed the highest release and stability compared to other formulae. The percent permeated across the rat intestine showed a 7.5-fold increase over free Celecoxib, and its lifetime was found to be greater than 18 months. The efficacy of free Celecoxib and oleogel formulae to treat rats with ulcerative colitis was done via the induction of ulcerative colitis (UC) through administration of 5% dextran sodium sulphate (DSS). Celecoxib besides its formulae significantly reduced the release of Leucine rich 2 glycoprotein (LRG), Myeloperoxidase (MPO), Tumor necrosis factor-α (TNF-α), proinflammatory cytokine expression, High mobility group box 1 (HMGB1), Nuclear factor kappa B (NF-ΚB), Trefoil Factor 3 (TFF3), Metalloproteinase-3 (MMP3), and miRNA31. Moreover, F3 significantly increased the colonic cAMP in DSS treated rats and reduced the intestinal inflammation beside healing of mucosa and restitution of the epithelium of the gastrointestinal tract.

The effect of some acrylic polymers on dissolution of celecoxib solid dispersion formulations.

OBJECTIVE: The purpose of the present study was firstly to identify the effectiveness of Eudragit® polymers (Eudragit® RL, RS, L100-55, L100, S100 and E100) in inhibition of celecoxib precipitation from buffer solutions (pH = 6.8). Furthermore, the influence of Eudragit® polymers on non-sink dissolution behavior of celecoxib from solid dispersions was investigated. METHODS: Solid dispersions were prepared by the rotary evaporation method. In vitro dissolution studies, FT-IR and differential scanning calorimetry were employed to characterize the formulations. RESULTS: The results revealed that Eudragit® E100, L100 and S100 inhibited precipitation of celecoxib efficiently. It is understood that crystallization during the dissolution of solid dispersions could happen through crystallization from solid matrix following contact with the dissolution medium or from the supersaturated solution produced following dissolution. The supersaturated drug concentrations attained from the dissolution of Eudragit®-celecoxib solid dispersions were almost similar, suggesting that crystallization from solid matrix did not occur readily. However, only solid dispersions containing efficient crystallization inhibitor polymers were able to maintain the supersaturated solution up to the end of the dissolution run. CONCLUSION: Results revealed that the principal mechanism of attaining supersaturated solution of celecoxib from solid dispersions was related to crystallization inhibition from solution not from solid matrix.

Simultaneous Determination of Celecoxib, Dezocine and Dexmedetomidine in Beagle Plasma Using UPLC-MS/MS Method and the Application in Pharmacokinetics.

BACKGROUND: An efficient, fast and sensitive ultra high-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) method for simultaneous determination of celecoxib (CEL), dezocine (DEZ) and dexmedetomidine (DEX) in beagle plasma were established. METHODS: The beagle dogs plasmawas precipitated by acetonitrile. The column was Acquity UPLC BEH C18 column and the mobile phase was acetonitrile-formic acid with gradient mode, and the flow rate was set at 0.4 mL/min. Under the positive ion mode, CEL, DEZ, DEX and Midazolam (internal standard, IS) were monitored by multiple reaction monitoring (MRM) as the following mass transition pairs: m/z 381.10→282.10 for CEL, m/z 246.20→147.00 for DEZ, m/z 201.10→94.90 for DEX, and m/z 326.10→291.10 for IS. RESULTS: This UPLC-MS/MS method had good linearity for CEL, DEZ and DEX. The RSDs of inter-day and intra-day precision were the values of 0.31-7.66% and 0.11-9.63%, respectively; the RE values were from -6.05% to 10.98%. The extraction recovery was more than 79%, and the matrix effect was around 100%. The RSDs of stability were less than 8.96%. All of them met the acceptance standard of biological analysis method recommended by FDA. CONCLUSION: This UPLC-MS/MS method is an effective tool for the simultaneous determination of CEL, DEX and DEX, and has been successfully applied to the study of pharmacokinetics in beagle dogs.

Amorphous Salts Solid Dispersions of Celecoxib: Enhanced Biopharmaceutical Performance and Physical Stability.

Numerous amorphous solid dispersion (ASD) formulations of celecoxib (CEL) have been attempted for enhancing the solubility, dissolution rate, and in vivo pharmacokinetics via high drug loading, polymer combination, or by surfactant addition. However, physical stability for long-term shelf life and desired in vivo pharmacokinetics remains elusive. Therefore, newer formulation strategies are always warranted to address poor aqueous solubility and oral bioavailability with extended shelf life. The present investigation elaborates a combined strategy of amorphization and salt formation for CEL, providing the benefits of enhanced solubility, dissolution rate, in vivo pharmacokinetics, and physical stability. We generated amorphous salts solid dispersion (ASSD) formulations of CEL via an in situ acid-base reaction involving counterions (Na+ and K+) and a polymer (Soluplus) using the spray-drying technique. The generated CEL-Na and CEL-K salts were homogeneously and molecularly dispersed in the matrix of Soluplus polymer. The characterization of generated ASSDs by differential scanning calorimetry revealed a much higher glass-transition temperature (Tg) than the pure amorphous CEL, confirming the salt formation of CEL in solid dispersions. The micro-Raman and proton nuclear magnetic resonance spectroscopy further confirmed the formation of salt at the -S═O position in the CEL molecules. CEL-Na-Soluplus ASSD exhibited a synergistic enhancement in the aqueous solubility (332.82-fold) and in vivo pharmacokinetics (9.83-fold enhancement in the blood plasma concentration) than the crystalline CEL. Furthermore, ASSD formulations were physically stable for nearly 1 year (352 days) in long-term stability studies at ambient conditions. Hence, we concluded that the ASSD is a promising strategy for CEL in improving the physicochemical properties and biopharmaceutical performance.

Evaluating Solubility of Celecoxib in Age-Appropriate Fasted- and Fed-State Gastric and Intestinal Biorelevant Media Representative of Adult and Pediatric Patients: Implications on Future Pediatric Biopharmaceutical Classification System.

Prediction of performance of traditional, reformulated, and novel oral formulations in adults and pediatrics is of great importance. This study was conducted to assess solubility of celecoxib in age-appropriate fasted- and fed-state gastric and intestinal biorelevant media, classify celecoxib into biopharmaceutical classification system (BCS), and assess the effects of age-related developmental changes in the composition and volume of gastrointestinal fluids on the solubility and performance of oral formulations containing celecoxib. Solubility of celecoxib was assessed at 37°C in the pH range specified by the BCS-based criteria in 13 age-appropriate biorelevant media reflective of the gastric and proximal small intestinal environment in both fasted and fed states in adults and different pediatric subpopulations. A validated HPLC-UV method was used to quantify celecoxib. Experimental and computational molecular descriptors and in vivo pharmacokinetic data were used to assign the permeability class of celecoxib. Celecoxib belonged to BCS class 2. The pediatric to adult solubility ratios were outside the 80-125% boundaries in 3 and borderline in 1 biorelevant media. Significant age-related variability could be predicted for oral formulations containing celecoxib intended for pediatric use. Findings of this study indicated that the criteria used in the adult BCS might not be directly applied to pediatric subpopulations.

Simultaneous Determination of Docetaxel and Celecoxib in Porous Microparticles and Rat Plasma by Liquid-Liquid Extraction and HPLC with UV Detection: in vitro and in vivo Validation and Application.

PURPOSE: A simple, rapid, sensitive, and reliable HPLC method with UV detection was developed and validated for simultaneous quantitation of docetaxel and celecoxib and paclitaxel for dissolution characterization and pharmacokinetic studies. METHODS: The HPLC assay was performed isocratically on a reversed-phase C18 µ-Bondapack column using a mobile phase of acetonitrile:water (45:55, v/v) at a flow rate of 1.2 mL/min, and the analytes were detected at 230 nm. Paclitaxel was used as an internal standard for analysis of plasma samples following simple liquid-liquid extraction with n-hexane:isoamyl alcohol (97:3). The method was validated for specificity, linearity, sensitivity, precision, accuracy, robustness, and in vitro-in vivo application. RESULTS: The retention times for docetaxel, paclitaxel, and celecoxib were 10.94, 12.4, and 16.81 min, respectively. The standard curves covering 0.1-1 µg/mL and 0.05-4 µg/mL were linear using dissolution medium and rat plasma, respectively. The limit of quantitation of the method was 50 ng/mL using 100 µL of rat plasma sample and injection of 50 µL of the residue. Within- and between-day precision and accuracy did not exceed 16.86% and 12.10%, respectively. This validated method was successfully used to quantify docetaxel and celecoxib simultaneously in the release study of docetaxel- celecoxib -loaded porous microparticles and pharmacokinetics studies. The methods were found to be simple, specific, precise, accurate, and reproducible. In this study, paclitaxel was used as the internal standard while dexamethasone, flutamide, and budesonide proved suitable alternative as an internal standard. CONCLUSION: Since docetaxel and celecoxib could be co-administered for the treatment of a wide range of cancers such as non-small cell lung carcinoma, the developed method is particularly advantageous for routine therapeutic drug monitoring and pharmacokinetic studies of these drugs.

Combined effect of sonophoresis and a microemulsion on the dermal delivery of celecoxib.

The aim of this study was to evaluate the intensity of sonophoresis at which the skin penetration of celecoxib was enhanced and to study the combined effects of sonophoresis and microemulsion application on the dermal delivery of celecoxib. The sonophoresis intensity that provided the highest skin penetration enhancement of celecoxib was 30 Watts/cm2. However, the combination of sonophoresis and the microemulsion resulted in a decrease in celecoxib skin penetration. The results of a confocal laser scanning microscopy study using the colocalization analysis of multifluorescently labeled particles revealed that the reduction in skin penetration of celecoxib from the combination of sonophoresis and a microemulsion resulted from a decrease in transfollicular penetration, which is the major skin absorption pathway of the microemulsion.

Development and evaluation of a biorelevant medium simulating porcine gastrointestinal fluids.

Simulated human intestinal media, have proved to be a useful biopharmaceutics tool as a dissolution media for predicting in vivo dissolution and pharmacokinetic profile in humans. During drug product development preclinical animal models are also required to assess drug product performance, and there is a need to develop species specific intestinal media to similarly predict in vivo pharmacokinetic profiles in each preclinical model. Pigs, are increasingly being used in preclinical drug development, however to date there is a lack of quantitative information about the composition of porcine gastrointestinal (GI) fluids. As a result, a porcine biorelevant medium has not yet been developed, which is essential to improve interpretation and forecast of preclinical results using biorelevant in vitro dissolution studies. GI fluid samples, were collected from landrace pigs, and characterized. Fasted State Simulated Intestinal Fluid of pigs (FaSSIFp) was developed based on the physiological composition of the GI fluids in terms of pH, buffer capacity, osmolality, surface tension, as well as the bile salt, phospholipid and free fatty acid content. This study demonstrated that FaSSIFp was superior at predicting the solubility of the six model drugs in porcine intestinal fluids (PIF). A markedly high correlation (r2 0.98) was observed between the solubility obtained in PIF and FaSSIFp, whereas poor correlation (r2 0.12) was found for the solubility of the model drugs between human FaSSIF and PIF. This confirms that species specific biorelevant intestinal media are crucial to provide more accurate predictions of pharmacokinetic studies in preclinical models. Additionally, the availability of a species specific intestinal medium offers the potential to improve in vitro-in silico approaches to predict in vivo absorption and to reduce the overall number of animals needed in oral drug product development testing.

Employment of Alginate Floating In Situ Gel for Controlled Delivery of Celecoxib: Solubilization and Formulation Studies.

Celecoxib (CXB) is a COX-2-selective nonsteroidal anti-inflammatory drug used to control pain and various inflammatory conditions. CXB has limited oral bioavailability and a slow dissociation rate due to its poor water solubility. In order to enhance the oral bioavailability of CXB and reduce the frequency of administration, the present study was aimed at enhancing the aqueous solubility of CXB by a cosolvency technique and then at formulating and evaluating a CXB in situ floating gelling system for sustained oral delivery. Three cosolvents, namely, PEG 600, propylene glycol, and glycerin, at different concentrations, were used to solubilize CXB. Particle size analysis was performed to confirm the solubility of CXB in the solutions. The floating in situ gel formulations were then prepared by the incorporation of the CXB solution into sodium alginate solutions (0.25, 0.5, and 1% w/v). Formulations, in sol form, were then in vitro characterized for their physical appearance, pH, and rheological behaviors, while formulations in gel form were evaluated for their floating behavior and in vitro drug release studies. FTIR spectroscopy was performed to examine drug-polymer interaction. The selected formula was evaluated biologically for its anti-inflammatory and analgesic activities. Results revealed that the less-polar solvent PEG 600 at 80% v/v had the highest solubilization potential, and it was used to optimize the in situ gel formulation. The candidate formula (F3) was found to have the highest sodium alginate concentration (1% w/v) and showed the optimum sustained release profile with the Higuchi model release kinetics. The results from the FTIR spectroscopy analysis showed noticeable drug-polymer molecular interaction. Moreover, F3 exhibited a significantly higher percentage of paw edema inhibition at 8 h compared with the reference drug (p < 0.05). Also, it showed a sustained duration of analgesia that persisted for the entire experimental time.

Self-Emulsifying Drug Delivery System of Celecoxib for Avoiding Delayed Oral Absorption in Rats with Impaired Gastric Motility.

This study aimed to develop a self-emulsifying drug delivery system (SEDDS) of celecoxib (CEL) for suppressed delay in oral absorption under impaired gastric motility. A pseudo-ternary phase diagram was constructed for the determination of the optimal component ratio in SEDDS of CEL (SEDDS/CEL), and the SEDDS/CEL was physicochemically characterized. A pharmacokinetic study on orally dosed CEL samples (5-mg CEL/kg) was carried out in normal and propantheline (PPT)-treated rats to mimic impaired gastric motility. SEDDS/CEL rapidly formed a fine emulsion with a mean size of 147 nm in distilled water and significantly improved the dissolution behavior of CEL under pH 1.2 condition with a 20-fold higher dissolved amount than crystalline CEL. In normal rats, orally dosed SEDDS/CEL provided a 4.6-fold higher systemic exposure than that of crystalline CEL, due to the improved dissolution properties of CEL. Crystalline CEL showed delayed and decreased oral absorption of CEL in PPT-treated rats as evidenced by a 6.9-h-delayed mean absorption time and only 12% of the systemic exposure of CEL compared with those in normal rats. In contrast, SEDDS/CEL enhanced the oral absorption of CEL with a 14.6-fold higher systemic exposure with significant suppression of delay in absorption than crystalline CEL even in PPT-treated rats. SEDDS/CEL could be an efficacious option for suppressing delay in CEL absorption even under impairment of gastric motility, possibly leading to rapid and reproducible management of severe acute pain.

Integration analysis of metabolites and single nucleotide polymorphisms improves the prediction of drug response of celecoxib.

INTRODUCTION: Pharmacogenetics and pharmacometabolomics are the common methods for personalized medicine, either genetic or metabolic biomarkers have limited predictive power for drug response. OBJECTIVES: In order to better predict drug response, the study attempted to integrate genetic and metabolic biomarkers for drug pharmacokinetics prediction. METHODS: The study chose celecoxib as study object, the pharmacokinetic behavior of celecoxib was assessed in 48 healthy volunteers based on UPLC-MS/MS platform, and celecoxib related single nucleotide polymorphisms (SNPs) were also detected. Three mathematic models were constructed for celecoxib pharmacokinetics prediction, the first one was mainly based on celecoxib-related SNPs; the second was based on the metabolites selected from a pharmacometabolomic analysis by using GC-MS/MS method, the last model was based on the combination of the celecoxib-related SNPs and metabolites above. RESULTS: The result proved that the last model showed an improved prediction power, the integration model could explain 71.0% AUC variation and predict 62.3% AUC variation. To facilitate clinical application, ten potential celecoxib-related biomarkers were further screened, which could explain 68.3% and predict 54.6% AUC variation, the predicted AUC was well correlated with the measured values (r = 0.838). CONCLUSION: This study provides a new route for personalized medicine, the integration of genetic and metabolic biomarkers can predict drug response with a higher accuracy.

Development of a Two-Compartment System In vitro Dissolution Test and Correlation with In vivo Pharmacokinetic Studies for Celecoxib.

The objective of this study was to develop a novel open-mode two-compartment system dissolution apparatus to simulate the dissolution and absorption of poorly soluble drugs and to establish an in vitro-in vivo correlation (IVIVC). Celecoxib (CEB) was selected as a model drug, and in vitro dissolution was performed using the novel dissolution apparatus with acetate buffers at pH 4.5 containing Tween 80 (0.15%, w/v), at a flow rate of 30 mL/min and an agitation rate of 50 rpm. Cumulative release of all formulations was incomplete at approximately 70-80%, which likely reflected in vivo dissolution. Corresponding pharmacokinetic studies were performed in which twelve healthy male subjects from two bioequivalence studies received either one immediate release (IR) dose of the test (test 1 or test 2) or the reference formulation (Celebrex®, 200 mg). Individual plasma profiles of the formulations were deconvoluted via the Wanger-Nelson method to obtain the mean absorption fractions. A level A correlation was successfully developed with a good R2. The Weibull equation was used to describe the in vitro dissolution and in vivo absorption kinetics. In vitro dissolution correlated with in vivo absorption was applied successfully to predict the in vivo plasma concentrations-time profiles of the CEB formulations. Compared with conventional methods, the novel dissolution device showed great potential for discriminating the dissolution between formulations and generic drugs, which may provide a tool for making in vivo predictions for next bioequivalence trials.

Continuous production of celecoxib nanoparticles using a three-dimensional-coaxial-flow microfluidic platform.

Increasing the dissolution rate of water insoluble drugs by decreasing the particle size of the drugs into nano-size is a well-known strategy. However, continuous production of drug nanoparticles with uniform particle size is critical for clinical application of the strategy. Here we report a simple microfluidic mixing method that can achieve continuous production of celecoxib nanoparticles with uniform particle size and high dissolution rate. A three-dimensional (3D) coaxial-flow microfluidic device was fabricated by assembling two coaxial aligned borosilicate glass capillaries on a glass slide, and a tapered glass capillary was inserted into another bigger cylindrical one with coaxial alignment. Celecoxib nanoparticles were prepared by the microfluidic device under the turbulent jet regime. The 3D-coaxial-flow pattern and high Reynolds number ensured the extremely short mixing time, consequently, resulted in the high throughput production of drug nanoparticles with uniform particle size. The obtained nanoparticles were spherical in shape, and showed superior dissolution rate compared with the coarse powder both in sink and non-sink conditions. The bioavailability of the water insoluble drug was also significantly improved by the reduction of particle size into nano-size.

Effects of Celecoxib on the QTc Interval: A Thorough QT/QTc Study.

PURPOSE: Celecoxib is a selective cyclooxygenase-2 inhibitor widely used in patients with osteoarthritis and rheumatoid arthritis. Recently, nonclinical data on the inhibition of human ether-à-go-go-related gene potassium channels by celecoxib were reported, but there is no compelling evidence for this finding in humans. The aim of this study was to assess the potential effects of celecoxib on cardiac repolarization by conducting a thorough QT study, which was designed in compliance with the related guidelines. METHODS: This randomized, open-label, positive- and negative-controlled, crossover clinical study was conducted in healthy male and female subjects. Each subject received, in 1 of 4 randomly assigned sequences, all of the following 3 interventions: celecoxib 400 mg once daily for 6 days; a single dose of moxifloxacin 400 mg, which served as a positive control to assess the assay sensitivity; and water without any drug, which served as a negative control. Serial 12-lead ECG and blood samples for pharmacokinetic analysis were collected periodically over 24 h. Individually RR-corrected QT intervals (QTcI) and Fridericia method-corrected QT intervals (QTcF) were calculated and evaluated. FINDINGS: Twenty-eight subjects were allocated to 1 of the 4 intervention sequences. The largest time-matched mean effects of celecoxib on the QTcI and QTcF were <5 ms, and the upper bounds of the 1-sided 95% CIs of those values did not exceed 10 ms. Moreover, none of the subjects had an absolute QTcI value of >450 ms or a change from baseline in QTcI of >60 ms after multiple administrations of celecoxib. The QTcI did not show a positive correlation with celecoxib concentrations in the range up to ~2700 µg/L. The overall effects of moxifloxacin on the QTcI and QTcF were enough to establish assay sensitivity. No serious adverse events were reported, with a total of 11 AEs reported in 8 subjects. IMPLICATIONS: Celecoxib caused no clinically relevant increase in the QT/QTc interval at the maximum dose level used in current practice settings. ClinicalTrials.gov identifier: NCT03822520.